Yersinia Enterocolitica and Yersinia Pseudotuberculosis

Home , Yersinia, Yersinia aldovae, Yersinia enterocolitica, Yersinia rohdei

4 Yersinia enterocolitica and Yersinia pseudotuberculosis

Maria Fredriksson-Ahomaa

1. CLASSIFICATION AND IDENTIFICATION Yersinia enterocolitica and Yersinia pseudotuberculosis are included in the genus Yersinia. These species were formerly included in the genus Pasteurella and later placed into the genus Yersinia, named in honor of the French bacteriologist A. J. E. Yersin, a discoverer of the plague bacillus (1). Y. pseudotuberculosis was the first species identified in this genus (2). This organism was described in 1889 as a disease in guinea pigs. How- ever, Y. pseudotuberculosis has shown to be the ancestor of Y. pestis, which was the cause of pandemic plague already during 541–767 AD (3). The Y. enterocolitica was identified in 1939 and named by Frederiksen in 1964 (4). The genus Yersinia is presently composed of 11 species, three of which can cause disease in humans and animals: Y. enterocolitica, Y. pseudotuberculosis, and Y. pestis (5–8). The three pathogenic species, the enteric foodborne pathogens Y. enterocolitica and Y. pseudotuberculosis, and Y. pestis are invasive pathogenic bacteria, which have a common capacity to resist nonspecific immune response and are lymphotrophic (9). These three pathogenic species differ considerably in invasiveness. While Y. enterocolitica and Y. pseudotuberculosis can cross the gastrointestinal mucosa to infect underlying tissue, Y. pestis is injected into the body through an insect bite, and thus, does not require penetrating any body surface on its own (9). The genus Yersinia is classified into the family Enterobacteriaceae, a group of Gram- negative, oxidase-negative and facultatively anaerobic bacteria. All bacteria, belonging to the genus Yersinia, are catalase-positive, nonspore-forming rods or coccobacilli of 0.5–0.8 × 1–3 Rm in size (5). These bacteria are lactose-negative and have the ability to grow at 0–4°C. Y. enterocolitica and Y. pseudotuberculosis are urease-positive and can be differentiated from other urease-positive Yersinia species on the basis of Voges–Proskauer test and their ability to ferment sorbitol, rhamnose, sucrose, and melibiose (Table 1). Y. enterocolitica is a heterogeneous species, which can be divided into six biotypes (1A, 1B, 2–5) on the basis of variations in biochemical reactions (10). Subdivision into these six biotypes can be done using the following reactions: pyrazinamidase activity, esculin hydrolysis, tween-esterase activity, indole production, and xylose and trehalose acidi- fication (Table 2). Biotypes 1B and 2–5 include strains that are associated with disease in man and animals when biotype 1A consists of nonpathogenic strains. However, strains

From: Infectious Disease: Foodborne Diseases Edited by: S. Simjee © Humana Press Inc., Totowa, NJ

79 80 Fredriksson-Ahomaa

Table 1 Biochemical Differentiation of Urea-Positive Yersinia Species After Incubation at 25°C for 18–20 h Reaction Voges– Species Proskauer Sorbitol Rhamnose Sucrose Melibiose Y. enterocolitica ++ + Y. pseudotuberculosis +/+/ Y. frederiksenii ++++ Y. intermedia +++++ Y. kristensenii + Y. aldovae +++ Y. rohdei + ++/ Y. mollaretii + + Y. bercovieri + +

Table 2 Biochemical Tests Used for Biotyping Y. enterocolitica and Y. pseudotuberculosis Isolates Y. enterocolitica Y. pseudotuberculosis Reactiona BTb1A BT1B BT2 BT3 BT4 BT5 BT1 BT2 BT3 BT4 Melibiose + + Citrate + Raffinose + Pyrazinamidase + Esculin + ++++ Tween ++ Indole +++ Xylose ++++ ++++ Trehalose +++++ ++++ aAll tests done at 25°C. bBT, biotype. of biotype 1A have constituted a sizeable fraction of strains from patients with gastroenteritis (11,12). Neubauer et al. (13,14) have demonstrated on the basis of the different DNA–DNA hybridization values and the 16S rRNA gene sequences that Y. enterocolitica should be divided into two subspecies, with one subspecies consisting of strains of biotype 1B, and the other of the remaining strains. Compared to Y. enterocolitica is Y. pseudotuberculosis a phenotypically more homo- geneous species. Nevertheless, Y. pseudotuberculosis can be divided into four biotypes according to their behavior in citrate, melibiose, and raffinose (15) (Table 2). No correlation of pathogenicity of Y. pseudotuberculosis with biotype was found in this study. However, melibiose-positive strains (biotypes 1 and 4) have shown to be more pathogenic than melibiose-negative strain (biotypes 2 and 3) (16). Yersinia 81

Table 3 Distribution of Pathogenic Y. enterocolitica Belonging to Different Bio-, Sero- and Phage Types Biotype Serotype Phagetype Host Distribution 1B O:4,32 Man United States O:8 X Man, pig, wild rodents Europe, Japan, North America O:13 Man, monkey North America O:18 Man United States O:20 Man, rat, monkey United States O:21 Man, rat flea North America 2 or 3 O:5,27 X Man, pig, dog, monkey Australia, Europe, Japan, North America O:9 X Man, pig, cattle, goat, Australia, Canada, Europe, dog, cat, rat Japan 3 O:1,2,3 I Chinchilla Europe, United States O:3 II Man, pig, dog Japan Man, pig, rabbit, rat Korea 4 O:3 VIII Europe, Japan IXA Man, pig, dog, cat, rat South Africa IXB North America 5 O:2,3 II Hare, goat, sheep, Europe, Australia rabbit, monkey

Y. enterocolitica and Y. pseudotuberculosis can be divided into numerous serotypes on the basis of antigenic variations in cell-wall lipopolysaccharide (LPS). Aleksic and Bockemühl (17) have proposed a revised and simplified typing scheme, which includes 20 antigenic factors for Y. enterocolitica alone. Serotype O:3 is most frequently isolated from humans in general (18–22). Other common serotypes obtained from humans include serotype, serotype O:9 and serotype O:8. However, several O-antigens, including O:3, O:8, and O:9, have been found in pathogenic and nonpathogenic strains (23). An accurate biochemical characterization is needed before or after serological typing that leads to correct assessment of the relevance of strains especially from foods and the environment, because related species and biotype 1A strains are widely distributed in these samples (24). The bioserotypes Y. enterocolitica differ in their geographical distribution, ecological niches, and pathogenic properties. The vast majority of clinical isolates belong to a relatively few bioserotypes. These bioserotypes have different geographical distributions (Table 3). Strains of biotype 1B serotypes O:4,32; O:8, O:13; O:18; O:20 and O:21 are frequently found associated with human diseases, mostly in the United States and Canada (25),but bioserotype 1B/O:8 has occasionally also been found in Japan and Europe (26–30). Strains that are largely responsible for human yersiniosis in Europe, Japan, Canada, and the United States belong to bioserotype 4/O:3 (25). Bioserotype 3/O:3 has been recovered in Japan (31) and China (32); serotypes O:9 and O:5,27 are more widely distributed (33). Non- pathogenic strains of biotype 1A (e.g., serotypes O:5; O:6,30; O:6,31; O:7,8; O:10, O:18; O:46 and nontypable trains) are distributed worldwide and are predominantly isolated from the environment, water, feces, and food (25). 82 Fredriksson-Ahomaa

Table 4 Distribution of Serotypes O:1 to O:5 of Y. pseudotuberculosis Isolated From Human and Nonhuman Sources No. of Country Source isolates 1a 1b 2a 2b 2c 3 4a 4b 5a 5b Ref. Japan Human 272 30 11 18 6 9 4 11 26 54 (42) 4 Pig 195 28 7 10 10 40 2 1 7 Dog 40 12 2 1 1 2 17 5 Cat 19 2 1 1 4 11 Rabbit 16 3 1 1 2 9 Rat 8 1 7 Water 39 2 2 2 12 5 16 Japan Human 45 14 1 2 28 (247) Raccoon dog 23 3 2 17 1 Wild mouse 9 2 7 Deer 8 1 6 1 Japan Water 110 9 5 2 1 14 19 54 6 (84) Italy Human 5 5 (127) Pig 8 1 7 Germany Human 52 21 10 7 3 7 2 2 (40) Hare 35 17 8 5 1 4 Bird 19 11 4 3 1 Sheep 5 2 2 1 Cat 5 2 2 1 Deer 4 1 1 2 Pig 3 1 3 Belgium Human 8 4 2 2 (124)

Y. enterocolitica can also be divided into phage types. Two schemes (Swedish and French) are used for phage typing of Y. enterocolitica (34). Of these, the French scheme has been used frequently and it recognizes 12 phage types: I–X (including IXa–c). The Swedish scheme recognizes seven phages (A1, A2, B1, B2, C32, C61, and E1) and is used less frequently. Neither of these schemes has produced a large number of distinct epidemiological types because many strains fall into the same phage types. Strains of bioserotype 4/O:3 and phage type VIII predominate in Europe and Japan (35), whereas phage type IXb has been isolated in Canada (36) and in the United States (37). Y. enterocolitica of bioserotype 1B/O:8 and phage type X, which is a typical North American type, has also sporadically been isolated in Japan (28,30). Because of the need to maintain stocks of biologically active phages and control strains, phage typing is available at only a few laboratories. A simplified antigenic scheme for serotyping of Y. pseudotuberculosis consists of 15 O-serotypes of which serotypes O:1 and O:2 are divided into three subtypes a, b, and c; and serotypes O:4 and O:5 into subtypes a and b (15,38). The serotypes of Y. pseudotuberculosis differ in their geographical distribution and ecological niches (Table 4). Yersinia 83

Serotypes O:1b and O:3 of Y. pseudotuberculosis have been isolated from the patients in Canada (39), whereas serotypes O:1a, O:1b and O:3 have most often been found in humans in Europe (40,41). In the Far East, serotypes O:1b, O:2a, O:2b, O:3, O:4a, O:4b, O:5a and O:5b, of which O:4b and O:5b are dominant, have been isolated from clinical samples (16,42). The relationship between pathogenicity and serological properties of Y. pseudotuberculosis is poorly understood (43). However, serotypes O:1 to O:5 have been isolated from humans, whereas serotypes O:6 to O:14 have been isolated from wild animals and from the environment, but not from the clinical samples (38).

2. RESERVOIRS Y. enterocolitica and Y. pseudotuberculosis are widely spread in nature. They have been isolated from many natural sources, such as animals, foods and the environment. Animals have long been suspected to be the reservoirs for Y. enterocolitica and Y. pseudotuberculosis, and thus, the source of human infections. Numerous studies have been carried out to isolate Y. enterocolitica from a variety of animals (44), including wild animals (45–55) and farm animals (45,56–60). However, most of Y. enterocolitica strains isolated from the animals differ both biochemically and serologically from strains isolated from humans with yersiniosis. Human pathogenic strains of Y. enterocolitica have frequently been isolated only from slaughter pigs, which have shown to be a reservoir of serotypes O:3. Serotypes 5,27, O:9, and O:8, which are also common among humans, have sporadically been isolated from pigs (33) (Fukushima et al. 1993). In Japan, serotypes O:3, O:8, and O:9 have been isolated from wild rodents, especially from field mice (61,62). Hayashidani et al. (62) have suggested that the small rodents living in the wild may be a source of Y. enterocolitica O:8 infection for humans in Japan. In this study, restriction endonuclease analysis of virulence plasmid patterns of wild rodents was indistinguishable from the patterns of humans. In France, Y. enterocolitica O:9 has frequently been isolated from the stools of cattle and goats in infected herds (63). The highest prevalence of Y. enterocolitica, belonging to serotypes associated with human yersiniosis, has been obtained in pig tonsils, with serotype O:3 being the most common (Table 5). Experimental infection of pigs has shown that Y. enterocolitica remains longer (64,65), and the number of isolates is higher (66) in tonsils than in feces. Y. enterocolitica of bioserotype 4/O:3 has a global distribution among the pig population, but the prevalence does vary between herds in many countries. This herd-wise distribution has been demonstrated by culture methods in Denmark, Norway, Finland, and Canada (58,67–71) and by serological tests in Denmark and Norway (72,73). By culture method, 18% (70) to 64% (69) of the herds have been shown negative for Y. enterocolitica 4/O:3. On the contrary, serological investigations have shown that 70–90% of the slaughter herds in Denmark and 63% in Norway are infected with serotype O:3, and that nearly all finishing pigs in infected herds are seropositive (72,73). Pet animals, such as cats and dogs, have been suspected of being reservoirs for human infections with Y. enterocolitica, because of their close contact with humans (34). However, strains of Y. enterocolitica 4/O:3 have only occasionally been isolated from dogs and cats (45,56,58,74–77). These strains have mostly been isolated from apparently healthy dogs (76,77). Dogs can asymptomatically carry Y. enterocolitica in the pharynx and excrete the organism in feces for several weeks after infection (78). 84 Fredriksson-Ahomaa

Table 5 Prevalence of Y. enterocolitica Belonging to Serotypes Associated With Human Disease in Slaughter Pigs Prevalence (%) of different serotypes No. of Country Sample samples O:3 O:5,27 O:8 O:9 Ref. Belgium Tonsils 54 33 (61) (95) Canada Tonsils 202 57 (28) 15 (7) (230) Feces 1420 235 (17) 25 (2) 1 (0.1) 9 (0.6) (71) Tonsils 291 63 (22) 1 (0.3) 2 (0.7) (65) Feces 291 17 (6) (65) Chile Tonsils 100 35 (35) (248) China Feces 510 37 (7) (32) Denmark Tonsils 400 149 (37) (58) Feces 1458 360 (25) (249) Finland Tonsils 185 68 (37) (250) Tonsils 210 122 (56) (251) Germany Tonsils 50 10 (60) (252) Feces 50 5 (10) (252) Italy Tonsils 106 43 (41) 2 (2) (93) Tonsils 150 19 (13) (253) Feces 150 4 (3) 1 (1) (253) Japan Throat 1200 88 (7) 1 (0.1) (254) Feces 1200 86 (7) 1 (0.1) (254) Netherlands Tonsils 86 33 (38) 3 (3) (91) Feces 100 16 (16) 1 (1) (91) Norway Tonsils 461 146 (32) 1 (0.2) (68) Spain Feces 110 6 (5) (255) United States Throat 3375 4 (0.1) 95 (3) (256)

Several studies have been carried out to isolate Y. pseudotuberculosis from farm animals, pets, and wild animals (Table 6). Y. pseudotuberculosis is a common inhabi- tant of the intestine in a wide variety of domestic and wild mammals. Although the host range is broad, the principal reservoir hosts are believed to be rodents, wild birds, and domestic animals (especially pigs and ruminants). Host genetics and age influence the susceptibility to disease. Y. pseudotuberculosis has been isolated from 11 species of animals in Japan (42). Of those, monkeys, goats, rabbits, and guinea pigs were diseased, where as cattle, swine, dogs, cats, hares, and rats were become the carriers. Jerrett et al. (79) reported that Y. pseudotuberculosis is one of the most common infectious cause of death among farmed deer in Australia. Y. pseudotuberculosis has frequently been isolated also from raccoon dogs, marten, and fox (80). Frolich et al. (81) reported antibodies against Yersinia spp. in 163 of 299 (55%) European brown hares by Western blotting in Germany. Y. pseudotuberculosis is also widely spread in the environment (soil and water) where it can survive for a long time. The environment itself is contaminated from the feces of infected animals, mainly rodents and birds (82). Y. pseudotuberculosis has been isolated from fresh water such as river, well, and mountain stream water at a considerable high rate (42,83,84). Yersinia 85

Table 6 Prevalence of Y. pseudotuberculosis in Animal Sources No. of No. of positive Sources samples samples % Country Reference Pig 544 14 2.6 Canada (36) 210 8 4.0 Finland (257) 217 1 0.5 Italy (127) 1200 52 4.3 Japan (254) 585 12 2.1 Japan (80) 60 1 0.2 Norway (258) Cattle 2639 185 7 Australia (259) 618 1 0.2 Japan (57) 330 1 0.3 New Zealand (260) Sheep 449 21 4.7 Australia (261) 66 2 3.0 New Zealand (260) Dear 153 29 18 Australia Jerrett et al. 1990 215 8 3.7 Japan (79) Dog 252 16 6.3 Japan Fukushima et al. (1984) 704 13 1.8 Japan (76) 176 5 2.8 Japan (80) Cat 318 4 1.3 Japan (262) 373 12 3.2 Japan (74) 724 64 8.8 Saudi Arabia (263) Hare 139 2 1.4 Japan (247) 474 6 1.3 Japan (80) Mouse 669 25 3.6 Japan (80) 107 9 8.4 China Zheng et al. (289) (1995) Rat 148 4 2.7 China Zheng et al. (289) (1995) 301 20 6.6 Saudi Arabia (263) Rabbits 148 4 2.7 China Zheng et al. (289) (1995) 70 1 1.4 Italy (127) Birds 900 1 0.1 Italy (127) 259 2 0.8 Japan (247) 108 5 4.6 Japan (80) 468 3 0.6 Sweden (264)

Food has often been suggested to be the main source of Y. enterocolitica, even though pathogenic isolates have seldom been recovered from food samples (29,85). Raw pork products have been widely investigated because of the association between Y. enterocolitica 4/O:3 and pigs (86–94). The isolation rate of Y. enterocolitica belonging to serotypes associated with human disease has been low in raw pork, except for pig tongues; the most common type isolated was bioserotype 4/O:3 (Table 7). The prevalence of bioserotype 4/O:3 has been exceptionally high in both pig tongues and minced meat in Belgium (95), where head meat including tonsils had been used for minced meat (96). Y. enterocolitica strains belonging to bioserotypes associated with human disease have been recovered only a few times from beef, poultry, and milk samples (94,97,98). In these cases, cross-contamination had probably occurred during the process, packaging, or handling. 86 Fredriksson-Ahomaa

Table 7 Isolation Rate of Y. enterocolitica Belonging to Serotypes Associated With Human Disease in Raw Pork Isolation rate (No. of positive samples) No. of Sample samples O:3 O:5,27 O:8 O:9 Country Reference Tongue 302 55 (165) 1 (3) Belgium (86) 37 33 (11) Canada (87) 31 2 (2) 19 (6) United States (37) 47 55 (26) Norway (265) 50 40 (20) Japan (266) 125 6 (8) Spain (255) 29 97 (28) Belgium (95) 40 15 (6) 5 (2) Netherlands (91) 55 25 (14) Germany (267) 86 2 (2) Italy (93) 99 80 (79) Finland (268) 20 75 (15) Germany (252) Offala 34 50 (17) Finland (107) 16 31 (5) Finland (268) 100 46 (46) Germany (252) Pork 91 1 (1) 13 (12)b 1 (1) Canada (87) 127 1 (1) Norway (89) 70 31 (22) 4 (3) Japan (266) 267 2 (6) Denmark (58) 50 24 (12) Belgium (95) 400 1 (3) 1 (0.3) Netherlands (91) 67 1 (1) 12 (8)b 4 (3) China (92) 48 2 (1) 2 (1) Germany (267) 40 5 (2) 10 (4) 2 (1) Ireland (97) 1278 5 (64) 1 (14) Japan (94) 255 4 (2) Finland (269) 300 2 (6) Norway (270) 120 12 (14) Germany (252) aOffal, including liver, heart, and kidney. bStrains belong to serotype O:5.

Inefficient isolation methods can be the reason for low prevalence rates of pathogenic Y. enterocolitica (99). The detection rate of pathogenic Y. enterocolitica in foods has shown to be clearly higher by PCR than by culturing (Table 8). In a case–control study, Y. enterocolitica 4/O:3 infections have been associated with eating raw or undercooked pork in 2 wk before the onset (96). In the United States, Y. enterocolitica 4/O:3 infections have been associated with the household preparation of chitterlings (intestines of pigs, which are a traditional holiday dish in the South), particularly among black children (18,100,101). Most of the Y. enterocolitica isolates recovered from the environmental samples, including slaughterhouses, butcher shops, fodder, soil, and water have been nonpathogenic in nature (52,55,58,67,90,102–105). However, strains of bioserotype 4/O:3 Yersinia 87

Table 8 Detection Rate of Pathogenic Yersinia enterocolitica in Natural Samples With PCR Detection rate Sample No. of samples (No. of positive samples) Reference Food Pig tongues 51 92 (47) (269) Minced pork 255 25 (63) (269) Pig offal 34 62 (21) (107) Porkb 300 17 (50) (270) Pig tongues 15 67 (10) (271) Ground pork 100 47 (47) (271) Ground beef 100 31 (31) (271) Tofu 50 12 (6) (271) Ground pork 350 38 (133) (272) Chitterlings 350 79 (278) (272) Environmental Water 105 10 (11) (111) Slaughterhouse 89 13 (12) (107) have occasionally been isolated from slaughterhouses (104,106,107), butcher shops (108,109), well-water used as drinking water (110), and sewage water (58). Sandery et al. (111) and Waage et al. (112) have shown using PCR that pathogenic strains of Y. enterocolitica can frequently be detected from the environmental waters.

3. FOODBORNE OUTBREAKS Yersiniosis has been observed in all continents but seems to be most common in Europe and Japan. Foodborne outbreaks of Y. enterocolitica and Y. pseudotuberculosis are not common and most of the infections are sporadic. However, foodborne outbreaks of Y. enterocolitica and Y. pseudotuberculosis may occur and have been reported from many countries (Table 9). Large outbreaks of Y. enterocolitica O:3 gastroenteritis has been documented in Japan and in the former Czechoslovakia (27,113). In all cases, Y. enterocolitica O:3 was the causative agent, but the source of infection went undetected. The food handler was expected to be responsible for the two nursery school outbreaks in the former Czechoslovakia (113). In the United States, after 1988, several outbreaks of serotype O:3 infections among infants attributed to chitterlings (a dish made from intestine) have been reported (18,29,101,114). In a case–control study of Y. enterocolitica infections among black infants, preparation of chitterlings was significantly (p < 0.001) associated with illness (101). In Europe, sporadic infections caused by bioserotype O:3 are common, but outbreaks of disease are uncommon. Because of the long incubation time and the predominance of cases going undiagnosed until 2–3 wk after the infection as arthritic symptoms, the source of infection was not traced in most cases. Y. enterocolitica 4/O:3 infection has been associated with consumption of raw or undercooked pork and untreated water in case–control studies (96,115,116). Several outbreaks of other serotypes have occurred in the United States; six of these were caused by serotype O:8 (Table 7). The outbreaks were associated with sick 88 Fredriksson-Ahomaa

Table 9 Foodborne Outbreaks of Y. enterocolitica and Y. pseudotuberculosis No. of Year Location Organism Cases Source Reference 1970 Norway Household YEa O:7,13 2 Well water (273) 1971 Finland Hospital YE O:9 7 Patient (274) 1971 Czechoslovakia School YE O:3 15 Unknown (113) 1972 Japan School A YE O:3 189 Unknown (275) 1972 Japan School B YE O:3 544 Unknown (275) 1972 United States Household YE O:8 15 Dog (117) 1976 United States School YE O:8 228 Chocolate milk (118) 1977 Japan Kindergarten YPb O:1b 82 Water (42) 1980 Japan School YE O:3 1051 Unknown (27) 1981 Japan School YE O:3 641 Unknown (27) 1981 Japan School YP O:5a 188 Vegetable juice (42) 1981 Canada Household YE O:21 3 River water Martin et al. (1992) 1981 United States Summer camp YE O:8 159 Milk powder (123) 1981 United States Residents YE O:8 50 Tofu (121) 1981 Finland School YP O:3 19 Unknown (276) 1981 Japan School YP O:5a 188 Vegetable juice (42) 1982 United States Brownie troops YE O:8 16 Bean sprouts (120) 1982 United States Residents YE O:13 172 Milk (122) 1982 Japan Mountain area YP O:4b 140 Water (42) 1984 Japan School YE O:3 102 Unknown (27) 1984 Japan Restaurant YP O:5a 39 Barbecue (277) 1984 Japan School YP O:3 63 Unknown (42) 1984 Japan Mountain area YP O:4b 11 Water (42) 1985 Japan School YP O:4b 60 Unknown (42) 1986 Belgium Day-nursery YE O:3 21 Unknown (181) 1986 Japan School YP O:4b 549 Unknown (42) 1987 Finland School YP O:1a 34 Unknown (180) 1989 United States Households YE O:3 15 Chitterlings (18) 1995 United States Residents YE O:8 10 Milk (98) 1998 Canada Households YP O:1b 74 Milk (126) 1997 Finland School YP O:3 36 Unknown (41) 1998 Finland School YP O:3 53 Unknown (41) 1998 Finland Cafeterias YP O:3 47 Iceberg lettuce (125) 1999 Finland School YP O:3 22 Iceberg lettuce (41) 2001 Finland Schools YP O:1, O:3 59 Chinese cabbage (41) 2001 United States Household YE O:3 12 Chitterlings (101) 2002 Croatia Oil tanker YE O:3 17 Unknown (278) aYE, Y. enterocolitica. bYP, Y. pseudotuberculosis. Yersinia 89 puppies (117), chocolate milk (118), powdered milk and chow mein (49), tofu (119), bean sprouts (120), and pasteurized milk (98). The source of infection in an inter-familial outbreak of Y. enterocolitica O:8 was suggested to be a female dog and its litter from sick puppies. The sequential onset of disease indicated that, once it had been introduced into the households, person-to-person transmission had occurred (117). In the tofu epidemic, the oriental soybean curd was probably packed in untreated spring-water contaminated with Y. enterocolitica. Samples of tofu, water supply and asymptomatic employees were positive for Y. enterocolitica O:8 (119). Inspection of the tofu plant revealed unsanitary conditions, including poor personal hygiene and unsanitary equipment. In addition, a rare serotype, O:13, has caused a large multistate outbreak in which the pasteurized milk was the common source (121,122). In case–control studies, drinking milk pasteurized by plan A was statistically associated with illness. In a familial outbreak of Y. enterocolitica O:21 in Canada, three people in a four-member family were involved. The family admitted of drinking unboiled water obtained directly from the river beside of their home (123). Y. pseudotuberculosis infections have been reported from all continents, but the incidence appears to be less frequent than for Y. enterocolitica. Most of the infections are sporadic and outbreaks are rare (124). Community outbreaks have mainly occurred in Finland and Japan (Table 9). The source of infection has remained unknown in most of the studies. However, iceberg lettuce was implicated as the vehicle of a widespread foodborne Y. pseudotuberculosis outbreak in Finland (125). One more outbreak has also been reported from Canada (126). Using case–control study, homogenized milk, pork, and fruit juice were identified as possible risk factors. Y. pseudotuberculosis 1b was isolated from stool specimen and a milk sample; however, the precise cause of this outbreak remained unknown. The frequency of Y. pseudotuberculosis in stool cultures from patients has shown to be low in Europe (124,127). In Japan, the frequency has shown to be clearly higher. The great differences between Europe and Japan are probably related to geographical differences, but can also be of technical factors including different culturing methods. Since 1970 in Japan, many reports have been made on sporadic infection and outbreaks associated with Y. pseudotuberculosis (42). Sporadic infection appears to be concen- trated in the 1–16-yr age group, with a peak at 1–2-yr-old children. For instance, Izumi fever, a childhood illness, is caused by Y. pseudotuberculosis. The highest incidence of Y. enterocolitica and Y. pseudotuberculosis infections in Europe has shown to be in young children of 1–5 yr age (22,40). The true incidence of Y. enterocolitica and Y. pseudotuberculosis infections is not known. The results of studies differ depending on the population materials and the diagnostic methods used. The isolation rates of Y. enterocolitica from stool cultures of patients with diarrhea in Finland, Canada, Chile, the Netherlands, New Zealand, Italy, and the United States have been reported to be 0.6–2.9% (19,128–130). The infection rate is probably much higher because only the most serious cases are registered. The prevalence of Y. enterocolitica O:3/O:9-specific antibodies was relatively high in Finland (19 and 31% by enzyme immunoassay and immunoblotting, respectively) and in Germany (33 and 43%) when healthy blood donors were studied (131). This may indicate a high amount of subclinical Yersinia infections in the healthy population. 90 Fredriksson-Ahomaa

Table 10 Virulence Determinants of Y. enterocolitica and Y. pseudotuberculosis Genomic origin Determinant Function Y. enterocolitica Y. pseudotuberculosis Plasmid ysc Yops Resistance to ++ phagocytosis yadA YadA Attachment, invasion + (+) Chromosome Inv Invasin Attachment, invasion ++ ail Ail Attachment, invasion + Serum resistance ++ yst Yst Fluid secretion in + intestine myf Myf Attachment + psa pH6 antigen Attachment, serum + resistance ypm YPM Stimulation of T-cells +

4. PATHOGENICITY Several genes contribute to the virulence of Y. enterocolitica and Y. pseudotuberculosis (Table 10). All fully virulent Yersinia harbor an approx 70-kb virulence plasmid, termed pYV (plasmid for Yersinia virulence), which is required for full expression of virulence (132,133). Chromosomal-encoded factors are also needed for virulence, because virulence functions are transferable by the virulence plasmid only to the plasmid-cured strains derived from parental strains (134,135). Virulence plasmids of pathogenic Yersinia are closely related to each other, sharing functional similarities and a high degree of DNA homology (136). The presence of pYV enables virulent Yersinia to survive and multiply in lymphoid tissues of their host (9). The pYV codes for an outer membrane protein YadA (Yersinia adhesin A), and a set of highly regulated secreted proteins, called Yops (Yersinia outer proteins). Yops are secreted by means of a type III secretion system, Ysc. Protein YadA is a major outer membrane protein, which forms a fibrillar matrix on the surfaces of Y. enterocolitica and Y. pseudotuberculosis (137), and is only expressed at 37°C (132). YadA is an important virulence factor of Y. enterocolitica, but seems to be dispensable for the virulence of Y. pseudotuberculosis (138). YadA plays a protective role in Y. enterocolitica with several functions (Table 11). The yop genes located on the pYV code for Yops, which were originally described as Yersinia outer membrane proteins because they were detected in the outer membrane fraction of bacterial extracts (139). Today, they are considered secreted proteins (140), which imbue Yersinia with the capacity to resist nonspecific immune response (141). Yops protect Yersinia from the macrophage by destroying its phagocytic and signaling capacities, and finally, inducing apoptosis. With the type III secretion system (Ysc), extracellularly located Yersinia that are in close contact with the eukaryotic cell deliver the toxic bacterial proteins (Yops) into the cytosol of the target cell. Genes specifying the type III machinery (ysc) are also located on the pYV. The yop and ysc genes are Yersinia 91

Table 11 Role of YadA in the Virulence of Y. enterocolitica Functions of YadA References Serum resistance (136) Surface hydrophobicity (279) Autoagglutination (280) Adhesion to epithelial cells (281) Hemagglutination (137) Binding to intestinal brush border membrane (282) Binding to fibronectin (283) Binding to collagen (284) Binding to intestinal submucosa (285) Resistance to killing by polymorphonuclear leukocytes (286) temperature- and calcium-regulated, being expressed maximally at 37°C in response to the presence of a low calcium concentration (141). All Yersinia strains carrying the virulence plasmid exhibit a phenotype known as low-calcium response because it manifests only when pYV-bearing strains are grown at 37°C in media containing a low concentration of Ca2+ (142,143). This growth-restriction phenomenon is associated with the massive production of Yops (9). Invasion of epithelial layers require at least two chromosomal genes, inv (invasion) and ail (attachment invasion locus) (144). The inv codes for Inv, an outer membrane protein, which appears to play a vital role in promoting entry into epithelial cells of the ileum during the initial stages of Y. enterocolitica and Y. pseudotuberculosis infections (145,146). Inv binds to G1 integrins and thereby mediates invasion into eukaryotic cells in vitro. This gene is found in all Yersinia spp.; however, nonpathogenic strains lack functional inv homologous sequences (147). Although the Inv protein is maximally synthesized at temperatures below 28°C, the Inv protein is equally well produced at 37°C under acidic conditions (145). The ail, in turn, codes for the surface protein Ail, which is produced at 37°C. The Ail also mediates resistance to the bactericidal effect of complement. In contrast to the inv, the ail is only found in Y. enterocolitica bioserotypes associated with the disease (148). Y. enterocolitica and Y. pseudotuberculosis migrate after ingestion through the stomach and the small intestine to the terminal end of ileum. The bacteria bind to the follicle-associated epithelium of the Peyer’s patches, which are a part of the gut- associated lymphoid tissue. Y. enterocolitica and Y. pseudotuberculosis penetrate the intestinal mucosa, through M cells, specialized cells involved in intestinal antigen uptake (149,150). Attachment and invasion of M cells are mediated by chromosomal determinants, Inv and Ail proteins, and plasmid determinant YadA (144,150). After penetration of the intestinal epithelium, enteropathogenic Yersinia colonizes the Peyer’s patches. The ability to survive and multiply within the lymphoid follicles and other tissue is associated with the presence of virulence plasmid, which is essential for the pathogenesis of Yersinia (151). Antiphagocytic properties of Yersinia are mainly mediated by Yop virulon products, which through bacterium–host cell contact subvert phagocyte function and enable survival and extracellular multiplication in host lymphoid tissue (133). Usually the infection is limited to the intestinal area, but 92 Fredriksson-Ahomaa sometimes the microorganisms drain into the mesenteric lymph nodes and give rise to a systemic infection. Both Y. enterocolitica and Y. pseudotuberculosis express fimbriae that are found on their surface (152). Y. enterocolitica synthesizes a fibrillar structure known as Myf (mucoid Yersinia factor). The chromosomal locus involves three genes: myfA, myfB, and myfC (153). Myf may serve as an intestinal colonization factor for Y. enterocolitica (154). The fimbriae in Y. pseudotuberculosis are called pH6 antigen, which is synthesized at 37°C under acidic conditions alone. The psa genes in the chromosome code for pH6 antigen (155). This antigen induces agglutination of erythrocytes, skin necrosis, upon intra-dermal injection in rabbits, and cytotoxicity for monocytes (152). Iron is an essential growth factor for the multiplication of almost all bacteria, including Y. enterocolitica and Y. pseudotuberculosis. The storage, transport, biosynthesis, and regulation of iron are important for the adaptation of Yersinia species to different environmental conditions (133,156). The ability to capture iron in vivo is one of the main factors that differentiate high- and low-pathogenic bacteria. Yersinia species have developed a variety of ingenious mechanisms for the retrieval of iron, including the ability to bind exogenous siderophores and produce their own siderophores, along with a range of other transport systems (156). One pathway for iron capture is to secrete small molecules called siderophores. These molecules chelate the iron bound to eucaryotic proteins and deliver the metal inside the cytosol of the bacteria. Yersiniabactin is a siderophore, which is synthesized by high-pathogenicity Yersinia only. Mouse-lethal serotypes of Y. enterocolitica, including serotype O:8, are able to synthesize the yersiniabactin. The yersiniabactin biosynthesis and transport genes are clustered within a region of the chromosome referred to as high-pathogenicity islands (HPI) (157). Low-pathogenicity Yersinia, including serotypes O:3 and O:9 of Y. enterocolitica, use exogenous siderophores like ferrioxamine, which is commonly used to treat patients with iron over-load, for capturing iron, thus enhancing their ability to disseminate in the host (152). These iron-regulation systems ensure the survival and multiplication of Yersinia in an iron-competitive environment. The chromosome of Y. enterocolitica, but not of Y. pseudotuberculosis, encodes a heat-stable enterotoxin, Yst (158). It is a 30-amino acid peptide, which resembles closely the heat-stable toxin of enterotoxigenic Escherichia coli. The role of Yst in the pathogenesis of Y. enterocolitica diarrhea in humans is at present uncertain. Nonpathogenic strains of Y. enterocolitica and strains of related species have been found to produce Yst using the infant mouse model (159), and the yst gene has been detected in strains of biotype 1A, Y. kristensenii and Y. intermedia (158,160). Absence of enterotoxin production in vitro at temperatures exceeding 30°C suggests that this toxin is not produced in the intestinal lumen. However, experimental evidence suggests that Yst may play an important factor involved in Y. enterocolitica-associated diarrhea in young rabbits (161). Robins-Brown et al. (162) investigated the pathogenicity of Y. enterocolitica O:3, including the role of Yst, using gnotobiotic newborn piglet model. There was evidence that enterotoxin may promote intra-intestinal proliferation of Y. enterocolitica, thus favoring increased shedding of bacteria and encouraging their spread between hosts. Urease is produced by all clinical isolates of enteropathogenic Yersinia. It is encoded by the urease gene complex (ure) in the chromosome (163). This enzyme hydrolyses urea to form carbonic acid and ammonia, leading to an increase in pH. Urease activity Yersinia 93 may contribute to the virulence by conferring acid tolerance and thereby enhancing bacterial survival in the stomach and other acidic environments (164). The decrease in virulence after intragastric inoculation of urease-negative mutant indicates that the main role of urease is during the initial stage of the bacterial infection, when the bacteria reach the stomach (165). LPS is a major surface component of the outer membrane of Gram-negative bacteria. In Yersinia, the genes directing the biosynthesis of LPS are chromosomally located. The full LPS molecule includes three structurally distinct parts: the lipid A anchored in the outer membrane, an oligosaccharide core, and the O-antigenic polysaccharide (O-antigen) (166). The lipid A part is believed to be responsible for endotoxin activity and to play a central role in sepsis and septic shock owing to Gram-negative bacteria. Skurnik et al. (167) have suggested that the outer core provides resistance against defense mechanisms, most probably those involving bactericidal peptides. Although the O-antigen is required for full virulence, its role has yet to be clarified (168). A total absence of O-antigen in Y. enterocolitica O:3 has been shown to reduce virulence in the infected mouse model (169). Y. pseudotuberculosis has been described to produce a superantigen, Y. pseudotuberculosis-derived mitogen (YPM). YPM-producing strains can be separated into three clusters of strains, which produce YPMa,YPMb, or YPMc encoded by the ypmA, ypmB, and ypmC, respectively (16,170). It has been demonstrated that distribution of the ypm genes among the strains from diverse geographical areas was in close correlation with the difference in the severity of clinical manifestations between the different areas (171). The frequency of YPMa-producing strains has shown to be higher in the Far East than in Europe, where systemic symptoms in the infected patients were less common compared with the Far East (171). Patients with systemic symptoms such as lympha- denopathy, transient renal dysfunction, and arthritis had shown to have significantly higher titers of anti-YPMa than patients with gastrointestinal tract symptoms alone (172). Y. pseudotuberculosis has been divided into six subgroups by Fukushima et al. (16). The presence of three virulence factors—YPM, HPI, and pYV—differed among these groups (Table 12). The pathogenicity of Y. pseudotuberculosis depended on the presence of YPMa, HPI, and pYV. The pYV is essential for pathogenicity. The difference in clinical manifestations of Y. pseudotuberculosis infection between the Far East and the western countries is related to the heterogeneity in the distribution of YPMa and HPI (Table 12). Most clinical strains were classified into two subgroups: Far East systemic type (group 3:YPMa+/HPI) and European gastroenteritis type (group 2:YPM/HPI+). The third group was European low-pathogenicity type (group 3: YPMa/HPI).

5. CLINICAL CHARACTERISTICS The enteric pathogens Y. enterocolitica and Y. pseudotuberculosis can cause illness ranging from self-limiting enteritis to fatal systematic infection. The major clinical features of infections with these microbes are similar and usually characterized by diarrhea, abdominal pain, and fever (Table 13). Sometimes the symptoms suggest acute appendicitis, and the patient is operated (173–175). The findings may include mesenteric lymphadenitis or terminal ileitis, more rarely true appendicitis is found. However, Lamps et al. (176) reported that both Y. enterocolitica and Y. pseudotuberculosis are important causes of granulomatous appendicitis and Yersinia infection may mimic 94 Fredriksson-Ahomaa

Table 12 Correlation Between Pathogenicity and Virulence Factors Among Y. pseudotuberculosis Strains Sub YPM group Location Pathogenicity YPMa YPMb YPMc HPI pYV 1 Far East High + ++ 2 Far East, West High ++ 3 Far East High + + 4 Far East NPa + 5 Far East, West Low +++ 6 Far East, West High + aNP, Nonpathogenic.

Crohn’s disease. Sometimes Yersinia infection is suspected on the basis of postinfec- tious complications such as reactive arthritis, eye inflammation, or erythema nodosum, after an infection, which may passed unnoticed (175,177–179). The clinical manifestations of the infection depend to some extent on the age and physical state of the patient, the presence or absence of underlying medical conditions, and the serotype of the organism (120). The symptom can even be faint and short-lived that yersiniosis is not diagnosed, despite fecal carriage (19,113,180,181). Gastroenteritis, caused by Y. enterocolitica, is the most frequent form of Yersiniosis and occurs most commonly in infants and young children (19,129,182). The incubation period ranges for 1 to 11 days (120). The minimal infective dose for humans has not been determined. The illness is generally mild and self-limiting persisting for 5–14 d, although diarrhea may persist several weeks, occasionally even for several months (120). Sometimes diarrhea may be bloody, and the fever may be high, especially in infants (101). Excretion of the organism in the stools continues for an average of 4 wk after cessation of symptoms, which may contribute to intra-familial spread (183). Intestinal yersiniosis may mimic acute appendicitis: abdominal pain in right lower quadrant, fever, and no diarrhea (100,184–186). Upon surgery, mesenteric lymphadenitis and true appendicitis may be distinguished by visual examination of the intestine and by light microscopy of the lymph-node biopsy (180,187). Macroscopically there is acute mesenteric lymphadenitis and terminal ileitis, and histologically normal or only mildly inflamed appendix. Unnecessary surgery could be avoided by abdominal ultra sound, computed tomography scanning or magnetic resonance imaging to distinguish between normal appendix and enlarged mesenteric lymph nodes, (184). The acute mesenteric lymphadenitis, caused by either Y. enterocolitica or Y. pseudotuberculosis,is a common symptom among children and young adolescents (120,175). Diarrhea and fever are usually milder in adults, but occasionally severe forms of gastrointestinal disease are seen. These include diffuse ulceration and inflammation of large and small bowel (117), peritonitis, toxic megacolon, intestinal perforation, ileocolic intussusception, and mesenteric vein thrombosis leading to intestinal necrosis and cholangitis. Also mild hepatitis and pancreatitis may be symptoms of yersiniosis. Yersinia infection may also be asymptomatic and pass unnoticed (180). Postinfection manifestations occur mainly in young adults (177). Less commonly, Y. enterocolitica may cause focal infection at extra-intestinal sites with or without bacteremia (188). Yersinia 95

Table 13 Clinical Symptoms Associated With Y. enterocolitica and Y. pseudotuberculosis Infections Bacteriological Country No. of patients Symptoms findings Reference Canada 74 Diarrhea 92%, fever 88%, abdominal YP O:1b (287) pain 76%, fatigue 68% Denmark 27 Diarrhea 93%, fever 71%, abdominal YE O:3 (21) pain 63%, vomiting 43% Finland 19 Abdominal pain 74%, fever 58%, YP O:3 (276) diarrhea 21% 34 Fever 53%, abdominal pain 38%, YP 1a (180) nausea 15%, diarrhea 15%, 47 Abdominal pain 89%, fever 68%, YP O:3 (125) diarrhea 45%, France 42 Diarrhea 71%, abdominal pain 64%, YE O:9 (63) only fever 29%, arthritis 14%, erythema nodosum 12% Japan 189 Abdominal pain 86%, fever 76%, YE O:3 (275) diarrhea 60%, nausea 24%, vomiting 4% 544 Abdominal pain 64%, fever 50%, YE O:3 (275) diarrhea 32%, nausea 25%, vomiting 11% 39 Fever 100%, abdominal pain 68%, YP O:5a (277) exanthema 68% The Netherlands 189 Enteritis 63%, extramesenteric form YE (221) 21%, arthritis and erythema nodosum 23% Norway 67 Diarrhea 97%, abdominal pain 77%, YE O:3 (288) fever 54% United States Abdominal pain 100%, Fever 100%, YE O:8 (98) 9 diarrhea 78%, nausea 61%, pharyngitis 22% 10 Diarrhea 100%, fever 80%, YE O:3 (101) vomiting 70% aYE, Y. enterocolitica. bYP, Y. pseudotuberculosis.

Cases of pneumonia, lung abscesses, empyema liver, splenic or renal abscesses, endocarditis, osteomyelitis, septic arthritis, and meningitis have all been reported (189–195). Exudative pharyngitis caused by Y. enterocolitis has also been reported (196,197). Rarely, in patients with a predisposing, underlying disease, such as diabetes mellitus and hepatic cirrhosis, or iron overload, or in young infants, infection with Y. enterocolitica may cause a septicemia illness (198,199). In Korea, several cases of septicemic form of Y. pseudotuberculosis infections have been reported (200). Hosaka et al. (30) reported Y. enterocolitica O:8 septicemia in an otherwise healthy adult. Sepsis can also occur during blood transfusion (201). One source of Y. enterocolitica-contaminated 96 Fredriksson-Ahomaa red blood cell concentrate has been reported to be a blood donor with asymptomatic bacteremia (202,203). Complications of Yersinia infection include reactive arthritis (ReA) and occasionally Reiter’s syndrome, erythema nodosum, eye inflammations such as uveitis and conjunctivitis, urethritis, balanitis, myocarditis, and glomerulonephritis (120,177,182,204–206). Postinfection complications usually develop within 1 wk to 1 mo after initial infection and may sometimes be the only obvious clinical manifestation of Yersinia infection (177). Arthritis and uveitis are associated with the presence of HLA-B27 antigen (207–211). Erythema nodosum is seen in about 10–30% of patients with yersiniosis (177). Y. pseudotuberculosis has also been associated with Kawasaki disease (mucocutaneous lymph node syndrome) an important illness of children in Japan and scarlet fever disease (42). Reactive arthritis triggered by infection with by Y. enterocolitica or Y. pseudotuberculosis is a frequent cause of acute arthritis predominantly in young and middle-aged patients (120,206). The patients may suffer from arthritis, after 1–3 wk of infection with or without gastroenteritis. Joint symptoms vary from mild arthralgia to severe arthritis. The arthritis is typically an asymmetric oligo- or polyarthritis with sudden onset affecting more often the joints of the lower extremities, such as knee, ankle, and toes, but sometimes also wrist and fingers (213,214). ReA is often migrating and painful. Lower back and muscular pains often coexist. The enteric arthritis is equally common among women and men (213). The mean duration of Yersinia-triggered arthritis has been reported to be between 3 and 6 mo. However, a substantial proportion of patients, about 20% in endemic area, experience a chronic course that continues longer than 12 mo (215). The most important factor, which influence prognosis, is HLA-B27. Patients with HLA-B27 have not only a more severe phase of arthritis but also a higher risk for chronic low back pain and sacroilitis, as well as chronic eye inflammation and development of ankylosing spondylitis (177). It has been suggested that Yersinia persist after the initial infection in those patients developing arthritis, even through the stool cultures become negative for Yersinia shortly after the onset of infection (179,209). Patients with Yersinia-triggered arthritis show persistent IgA antibodies against Yersinia outer membrane proteins, which is may be the result of chronic stimulation of the gut associated lymphoid tissue by persistent Yersinia (216). Bacteria have not been found in affected joint but degraded LPS of Yersinia have been detected in the joint synovium (214,217).

6. CHOICE OF TREATMENT Yersinia strains are usually susceptible in vitro to co-trimoxazole, aminoglycosides, tetracyclines, chloramphenicol, third-generation cephalosporins, and quinolones (218–221). Y. enterocolitica produces frequently G-lactamases and is usually resistant to penicillins and to first-generation cephalosporins (193,221,222). In contrast, Y. pseudotuberculosis is susceptible to penicillins because it lacks G-lactamase. The great majority of Yersinia enterocolitis and acute mesenteric adenitis in immuno- competent hosts are self-limiting, and supportive care including fluid and electrolyte replacement is usually sufficient. Antimicrobial therapy has not been proved to be essential or efficient in the treatment of uncomplicated enterocolitis or the pseudoappendicular syndrome. In a placebo-controlled, double blind evaluation of co-trimoxazole therapy Yersinia 97 for Y. enterocolitica enterocolitis in children, treatment failed to shorten the clinical or bacteriologic course of the illness (183). A prospective study has been undertaken to evaluate the incidence, course, effect of treatment and outcome of patients with Y. enterocolitica infections (221). A total of 189 patients were followed. The majority of the patients with enteritis recovered without antibiotic treatment. However, the duration of enteritis was not significantly influenced by antibiotic treatment. Systemic infection, focal extraintestinal infection, and enterocolitis in immuno- compromised patients should be treated with antimicrobial therapy. In an experimental model of systemic Y. enterocolitica infection in mice, doxycycline, and gentamicin were effective in stopping the proliferation of serotype O:8, where as cefotaxime and imipenem were ineffective. Cover and Aber (120) recommended a combination of doxycycline and an aminoglyside for the treatment of patients with bactremia until antimicrobial-susceptibility tests have been performed. Co-trimoxazole, tetracyclines, fluoroquinolones, and aminoglycosides are usually effective in the treatment of septicemic infection and tissue abscesses in liver and spleen (223). Ciprofloxacin has shown to be more appropriate for Yersinia osteomyelitis, and co-trimoxazole, chloramphenicol, or third-generation cephalosporin is preferable for central nervous infection. However, fluorochinolones should be considered as a first-line therapy for invasive infection related to Y. enterocolitica (193,222). Before, streptomycin or sulphamethoxazole have been recommended for the treatment of severe and acute mesenteric adenitis or enteric fever-like syndrome (224), but these are not any more recommended for the treatment of Y. enterocolitica infections. However, the antibiotic therapy should always be based on the results of the antibiogram. ReA patients are treated symptomatically with nonsteroidal anti-inflammatory drugs or, in severe cases, with steroids, and those with chronic courses are treated with second- line drugs, such as sulfasalazine (215). There was a tendency towards faster remission and relief of pain in patients with ReA receiving ciprofloxacin (216). No effect of ciprofloxacin treatment on arthritis triggered by Yersinia was reported by Sieper et al. (215). Oili et al. (225) have described two patients with acute ReA caused by Y. enterocolitica who were treated with infliximab with a good response in the acute phase. However, the influence of new drugs on the prognosis of patients with ReA remains to be evaluated.

7. RESISTANCE EPIDEMIOLOGY A number of antimicrobial agents are active in vitro against Y. enterocolitica and Y. pseudotuberculosis strains isolated from human (218,226–228) and nonhuman sources (219,224,229,230). These include aminoglycosides (e.g., gentamicin, streptomycin, tobramycin, and kanamycin), the third-generation cephalosporins (e.g., ceftriaxone, caftazidime, and cefotaxime), co-trimoxazole, tetracyclines, chloramphenicol, fluoroquinolones (e.g., ciprofloxacin, norfloxacin, and ofloxacin), imipenem, and aztreonam (227–229,231–233). Isolates from human, environmental, and animal sources have essentially equal susceptibility patterns (234). Yersinia strains are generally resistant to G-lactamase-sensitive penicillins, such as ampicillin, cloxacillin, carbenicillin and ticarcillin, the first-generation narrow-spectrum cephalosporins, erythromycin, clidamycin, and vancomycin (229,234,235). However, some differences in antimicrobial susceptibilities of Y. enterocolitica strains to G-lactam antibiotics have been detected among different biotypes (Table 14) and serotypes (220). 98 Fredriksson-Ahomaa

Table 14 Antibiotic Susceptibility of Different Biotypes of Y. enterocolitica Biotype Antibiotic 1A 1B 2 3 4 5 Reference Ampicillin Sa Rb R (234) Amoxicillin/ R S R R S S (231) clavulanate RRS(226) SR S (234) RRRRS (227) Carbenicillin R S R (234) RSR(226) Cefixime R S R R S S (231) Cefoxitin R R S S (226) R S R SSS (231) Fosfomycin R R S S S S (231) Ticarcillin R R R S R R (231) RSR(226) RS R (234) aSensitive. bResistant. Most strains of biotype 4 have shown to be sensitive to amoxicillin/clavulanate and to third-generation cephalosporins, but resistant to ampicillin, carbenicillin, ticarcillin, and cephalotin (226,227,231,234). In comparison, most strains of biotype 2 and biotype 3 have shown to be more susceptible to both carbenicillin and ticarcillin, but resistant to amoxicillin–clavulanic acid (219,226,227,231,234). Strains of biotype 1B, on the other hand, have shown to exhibit high rates of suscebtibility to ampicillin and amoxicillin– clavulanic acid, but resistance to carbenicillin, ticarcillin, and cephalothin, whereas strains of biotype 1A have shown to be resistant to amoxicillin–clavulanic acid (226,231,234). The differences in antimicrobial susceptibility among Y. enterocolitica strains of different biotypes are largely attributed to G-lactam resistance, which is mediated by the production of two chromosomally mediated G-lactamases (A and B) (236,237). Lactamase A is a noninducible broad-spectrum enzyme and lactamase B is an inducible cephalosporinase (238). Y. enterocolitica strains belonging to bioserotype 4/O:3, phage types VIII (from Europe, Asia, and Brazil) and IXa (from South Africa and Hungary) have shown to be homogenous in expression of G-lactamase, with all strains producing both enzyme A and enzyme B. However, Y. enterocolitica 4/O:3/IXb strains isolated in Canada have shown to produce both enzyme A and enzyme B when Y. enterocolitica 4/O:3/IXb strains from Australia and New Zealand lacked the cephalosporinase enzyme B (239). These two lactamases account for resistance to ampicillin, cephalothin, carbenicillin, and ticarcillin. Most of Y. enterocolitica strains of less- commonly isolated biotypes 2 and 3 lack the enzyme A, which may explain the sensitivity to carbenicillin and ticarcillin. Emerging antimicrobial resistance phenotypes have been recognized among multiple zoonotic pathogens, including Y. enterocolitica (240). Antimicrobial agents are used in high quantities for therapy, prophylaxis and growth promotion in modern food-animal Yersinia 99 production (241). Almost all Y. enterocolitica strains from pigs examined by Aarestrup et al. (241) in Denmark were resistant to ampicillin but susceptible to streptomycin and sulphonamides. However, a limited number of Y. enterocolitica strains were resistant nalidixic acid and a single isolate to gentamicin and spectinomycin. In the last few years, clinical isolates that are resistant to chloramphenicol, streptomycin, sulfonamides, co-trimoxazole, and nalidixic acid have been reported (223,242–244). Sanchez et al. have reported the emergence of nalidixic acid-resistant Y. enterocolitica around Madrid in Spain (244). Prats et al. (223) showed that the rate of resistance among Y. enterocolitica O:3 strains has increased up to 90% for streptomycin and sulfonamides, 70% for trimethoprim–sulfamethoxazole, 60% for chloramphenicol, and 5% for nalidixic acid. Kelley et al. (245) studied 22 Y. enterocolitica strains recovered from poultry litter in the United States and found 4 out of 22 isolates that exhibited multi-resistance to bacitracin, penicillin, streptomycin, and tetracycline. In total, 13 out 22 isolates were resistant to tetracycline. Funk et al. (246) reported resistance to oxytetracycline also from slaughter swine in the United States. Tetracyclines are commonly added to swine feeds. Oxytetra- cycline resistance is often plasmid mediated and could be impacted by on-farm antibiotic usage. Resistance to sulfonamides (except trimethoprim–sulfamethoxazole) is widespread (67,246), but Preston et al. (234) found a high rate of susceptibility to sulfamethoxazole. Sulfonamides have been used for growth promotion and prevention of diseases in swine. The resistance to sulfonamides among slaughter swine may indicate acquired- resistance from their use in animal feeds (229).

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